Alzheimer's Disease (AD) risk is reduced by fish consumption, possibly due to long chain omega 3 fatty acids (eicospentaenoic acid (EPA) and docosahexaenoic acid (DHA). Lab chows typically contain abundant soy and fish and are omega-3 fatty acids sufficient raising the issue of whether omega 3 in the chow influences AD pathogenesis in lab models. Aged APPsw AD model mice were placed on a DHA-depleting "Bad" diet with safflower oil as the principal fat. With no evidence for neuron or synaptophysin loss, DHA depletion increased oxidative damage, caspase-cleaved actin and deficits in PSD-95 and the dendritic spine actin-binding protein, drebrin. The effect was transgene-dependent, suggesting that the "Bad" diet is permissive for a selective APP transgene-induced post-synaptic deficit. Only Tg(+) mice on "Bad" diet developed major deficits in mRNA and protein associated with postsynaptic function and memory, including neuroprotective principal investigator3K p85 that regulates both caspase and tau kinase activation. Whether dietary DHA's neuroprotective effects come from regulation of phosphatidylserine levels and principal investigator3-K or from lipoxygenase derived DHA metabolites (neuroprotectin Dl) remains unknown. Amyloid pathology was also reduced by DHA supplementation, but the mechanisms involved also remain unclear: DHA did not induce transthyretin (TTR), an anti-amyloid protein that reduces AD pathology and has been reportedly induced by fish oil. Currently fish oil supplementation is a relatively safe and cheap alternative to either increased fish consumption with risks of mercury and lipid soluble toxins or more expensive algae-derived DHA supplementation. We hypothesize that: 1) Fish oil supplementation will synergize with the antioxidant curcumin and work as well or better than DHA in our AD model in controlling synaptic marker loss. 2) Fish oil will have similar anti-amyloid activities as DHA, but also induce TTR and be more effective in controlling amyloid. 3) EPA supplementation will induce only a subset of the protective effects of DHA. 4) Fish oil or DHA will increase principal investigator3-K pathway inhibition of GSK36 and tau pathology. We propose to test these hypotheses in transgenic and culture models with and without baseline omega-3 depletion providing more information on mechanism, active ingredient and the utility of marine oil and antioxidant supplementation relevant to the prevention and treatment of Alzheimer's disease. [unreadable] [unreadable] [unreadable]